Better care for older patients with complex multimorbidity and frailty: a call to action
Authors: Luigi Ferrucci, Ronald Kohanski
Journal: The Lancet Healthy Longevity (2022)

Over the past few decades, the ageing of the population has led to profound changes in fundamental aspects of how our society is organised. These include changes in family structure and living conditions, economic priorities, social security, and health care. There are reasons to celebrate these transformations. Extended longevity comes from improved living conditions and medical treatments.1Scott AJ The longevity society.Lancet Healthy Longev. 2021; 2: e820-e827Summary Full Text Full Text PDF Scopus (5) Google Scholar The treatment of cardiovascular risk factors has benefited middle aged and older people, for example, and new more effective treatment of acute cardiovascular events has substantially reduced their morbidity and mortality.2Joseph P Leong D McKee M et al.Reducing the global burden of cardiovascular disease, part 1: the epidemiology and risk factors.Circ Res. 2017; 121: 677-694Crossref PubMed Scopus (409) Google Scholar Emerging chemotherapy and immunotherapeutic treatments are giving new hope to patients with cancer, the second most frequent cause of death in the adult population.3Allemani C Matsuda T Di Carlo V et al.Global surveillance of trends in cancer survival 2000–14 (CONCORD-3): analysis of individual records for 37 513 025 patients diagnosed with one of 18 cancers from 322 population-based registries in 71 countries.Lancet. 2018; 391: 1023-1075Summary Full Text Full Text PDF PubMed Scopus (1945) Google Scholar These medical successes are celebrated by prestigious prizes and honours and highlighted by the media, and rightly so. Yet, a side-effect of this progress is often overlooked. Despite landmark successes in the prevention and treatment of specific diseases, the care of older patients with complex multimorbidity, defined as two or more chronic medical conditions in the same individual, which represents the majority of older patients in the health-care system, has changed little and remains substantially unsatisfactory. This bitter reality contrasts with knowledge gained from research on ageing, which is expanding more than ever before, both in breadth and depth. New academic institutions, as well as profit and non-profit foundations dedicated to the study of ageing, emerge almost monthly. Scientific articles on biological and clinical aspects of ageing are often published in highly ranked scientific journals. That such growing knowledge about ageing has yet to be translated to the care of older patients with complex multimorbidity and frailty is disconcerting, and it therefore might be useful to speculate on why this is the case.For almost a century, most of medical diagnosis, prevention, and treatment have focused on specific diseases. Educational systems, medical departments, and research institutes, as well as the process for approval of new diagnostics and therapeutics, are organised around a disease model. Only relatively recently has the medical community recognised that patients with multiple comorbidities absorb the bulk of resources in the medical system.4Cassell A Edwards D Harshfield A et al.The epidemiology of multimorbidity in primary care: a retrospective cohort study.Br J Gen Pract. 2018; 68: e245-e251Crossref PubMed Scopus (185) Google Scholar In older patients, multimorbidity is not merely the stochastic co-emergence of multiple medical conditions that, at least apparently, have different pathophysiologies. Rather, there is evidence that some individuals have a global susceptibility to multiple diseases. Finally, although the accumulation of pathology occurs progressively over the lifetime, the diagnosis of diseases only becomes possible when the accumulation of pathology is beyond the threshold of compensation and the signs, symptoms, and functional impairments become manifest. Thus, most patients (older and younger) who approach the medical system because of alarm signs or symptoms are likely to be affected by other subclinical pathologies. Because of the mantra one symptom—one disease emphasised in medical education and the increasingly shorter time that physicians can dedicate to patients, hidden comorbidity is often ignored until it is no longer silent, and patients come back to the medical system with complex multimorbidity, or even frailty. Our ability to offer cures and care for such patients is, at best, mediocre.5Walston J Bandeen-Roche K Buta B et al.Moving frailty toward clinical practice: NIA Intramural Frailty Science Symposium summary.J Am Geriatr Soc. 2019; 67: 1559-1564Crossref PubMed Scopus (82) Google Scholar Only over the past 10 years have the guidelines for the diagnosis and treatment of specific diseases developed by medical societies begun to account for co-morbididity, but such guidelines almost never account for multimorbidity. There is evidence that comorbidity, especially in older people who also have physical and cognitive impairments, hides the clinical presentation of emerging pathology, blunts responses to treatment, and results in unexpected adverse outcomes, sometimes even because of iatrogenesis.6Whitty CJM MacEwen C Goddard A et al.Rising to the challenge of multimorbidity.BMJ. 2020; 368: l6964Crossref PubMed Scopus (91) Google ScholarThe treatment of older patients with complex multimorbidity and frailty is a challenge for health-care systems around the world. Yet, emerging technology and new research give rise to some hope for the future. The movement of so-called geroscience proposes that multimorbidity and frailty are the cumulative expression of ageing and that understanding the biological mechanisms of ageing will open the door to new therapeutic possibilities.7Sierra F Caspi A Fortinsky RH et al.Moving geroscience from the bench to clinical care and health policy.J Am Geriatr Soc. 2021; 69: 2455-2463Crossref PubMed Scopus (10) Google Scholar Expanding the clinical use of deficit accumulation indexes (DAIs) might be a first step in the right direction.8Rockwood K Mitnitski A Frailty in relation to the accumulation of deficits.J Gerontol A Biol Sci Med Sci. 2007; 62: 722-727Crossref PubMed Scopus (1491) Google Scholar DAIs are agnostic regarding which diseases and health deficiencies are present and provide a global metric of health that can alert clinicians to possible impending health deterioration. At the global level, these indices can help to uncover health disparities in particular groups and inform clinical guidelines and policies. However, there is growing evidence that diseases emerge in clusters, not necessarily due to a common cause (other than ageing per se), and identification of these clusters would be another important tool in the clinical management of older people.9Vetrano DL Roso-Llorach A Fernández S et al.Twelve-year clinical trajectories of multimorbidity in a population of older adults.Nat Commun. 2020; 11: 3223Crossref PubMed Scopus (49) Google Scholar For example, clinical trials that use metformin as a geroprotector,10Wang C-P Lorenzo C Habib SL Jo B Espinoza SE Differential effects of metformin on age related comorbidities in older men with type 2 diabetes.J Diabetes Complications. 2017; 31: 679-686Crossref PubMed Scopus (69) Google Scholar, 11Kulkarni AS Aleksic S Berger DM Sierra F Kuchel GA Barzilai N Geroscience-guided repurposing of FDA-approved drugs to target aging: a proposed process and prioritization.Aging Cell. 2022; 21: e13596Crossref PubMed Scopus (3) Google Scholar such as the TAME trial, consider multimorbidity as one of the primary outcomes. Looking at specific clusters of coexisting diseases identified in large epidemiological studies might be important to better define the outcomes of these trials.Translating measures of the fundamental mechanisms of ageing, identified as the hallmarks or pillars of ageing,12López-Otín C Blasco MA Partridge L Serrano M Kroemer G The hallmarks of aging.Cell. 2013; 153: 1194-1217Summary Full Text Full Text PDF PubMed Scopus (7255) Google Scholar to humans also has great potential. We can now quantify thousands of proteins, metabolites, and other biomarkers in a few drops of blood, and algorithms for the detection of many different chronic diseases, as well as accelerated ageing based on these biomarkers, are being developed and validated in large populations. Specificity and predictive value are being replicated in multiple populations, suggesting that their application to clinical practice is getting closer.13Rutledge J Oh H Wyss-Coray T Measuring biological age using omics data.Nat Rev Genet. 2022; 10 (published online June 17.)https://doi.org/10.1038/s41576-022-00511-7Google Scholar If the technologies for assessing these biomarkers could be scaled up to be relatively inexpensive and high throughput, these biomarkers could be routinely applied to all people who contact a health professional because of an emerging medical problem. The information collected from these biomarkers and other technologies, as well as therapeutic choices and outcomes, could be fed to an artificial intelligence (AI) system that over time sorts what has worked from what has not, even for an individual, to progressively enhance the diagnostic and therapeutic value of longitudinally collected information. In the future, this powerful information system could also provide more information pertaining to the expected outcomes of different therapeutic choices to health-care professionals and patients so they can make more informed decisions. Introducing a time dimension into clinical assessment is possibly the most important reason for having access to electronic medical records. Enhancing health care through personalised medicine, each patient could be viewed as a longitudinal case study, with the expectation that monitoring the change of a clinical value, even within normal values, would reveal and allow for addressing subclinical morbidities. Given the possible feedback loop between morbidity and the rate of ageing, addressing incipient disease in the preclinical period might be a powerful strategy to slow down the rate of ageing and prevent or delay its deleterious consequences. Over time, treatment approaches that result in poor outcomes could be weeded out and new therapeutic approaches that become available can be tested in real-world situations. Those who care for older adults are fully aware that behavioural, social, and environmental factors can strongly affect the outcomes of older patients with complex multimorbidity and disability and this information could be included in the aforementioned surveillance system.The approach to health and health care described here is quite different from what we have used up to this point, but new problems call for new solutions. Early detection of subclinical pathology and the development of biomarkers that capture the rate of ageing are powerful assets that might expand prevention beyond the boundaries of specific diseases and provide people with additional years of healthy life. An approach to health problems that is not based on disease nosology, but rather biomarker algorithms constantly refined by an AI-based surveillance system, might also provide a better approach to the care of older patients with incipient or presenting complex multimorbidity and disability. Thus, the tools to face the challenge posed by complex older patients with multimorbidity and frailty are potentially already available, and what is needed is a strong push for their translation to clinical application and care. A crucial step is to close the gap between the so-called geroscientists and the health professionals who take care of older patients. We have all heard or read that "these new findings have strong translational potential", but in most instances there are no geriatricians or other health professionals among the audience or readership to react to these statements. Finding new and more efficient ways to connect basic research on ageing with the care of older patients is essential to orient research in the right direction and toward topics that hamper the successful care of older patients. Only those who deal daily with the complexity of problems presented by these patients can provide this information. Geriatricians, health-care providers, and patients should be the primary beneficiaries of this science and, therefore, it seems logical that they should be strongly involved as soon as possible.These few considerations represent what we believe is a roadmap to make progress in this field, but we call for visionary researchers to provide new ideas for the development of novel programs that might improve the health and quality of life in this patient population, which will exponentially grow in the future. It is already late, and we should not wait any longer to have this discussion. Over the past few decades, the ageing of the population has led to profound changes in fundamental aspects of how our society is organised. These include changes in family structure and living conditions, economic priorities, social security, and health care. There are reasons to celebrate these transformations. Extended longevity comes from improved living conditions and medical treatments.1Scott AJ The longevity society.Lancet Healthy Longev. 2021; 2: e820-e827Summary Full Text Full Text PDF Scopus (5) Google Scholar The treatment of cardiovascular risk factors has benefited middle aged and older people, for example, and new more effective treatment of acute cardiovascular events has substantially reduced their morbidity and mortality.2Joseph P Leong D McKee M et al.Reducing the global burden of cardiovascular disease, part 1: the epidemiology and risk factors.Circ Res. 2017; 121: 677-694Crossref PubMed Scopus (409) Google Scholar Emerging chemotherapy and immunotherapeutic treatments are giving new hope to patients with cancer, the second most frequent cause of death in the adult population.3Allemani C Matsuda T Di Carlo V et al.Global surveillance of trends in cancer survival 2000–14 (CONCORD-3): analysis of individual records for 37 513 025 patients diagnosed with one of 18 cancers from 322 population-based registries in 71 countries.Lancet. 2018; 391: 1023-1075Summary Full Text Full Text PDF PubMed Scopus (1945) Google Scholar These medical successes are celebrated by prestigious prizes and honours and highlighted by the media, and rightly so. Yet, a side-effect of this progress is often overlooked. Despite landmark successes in the prevention and treatment of specific diseases, the care of older patients with complex multimorbidity, defined as two or more chronic medical conditions in the same individual, which represents the majority of older patients in the health-care system, has changed little and remains substantially unsatisfactory. This bitter reality contrasts with knowledge gained from research on ageing, which is expanding more than ever before, both in breadth and depth. New academic institutions, as well as profit and non-profit foundations dedicated to the study of ageing, emerge almost monthly. Scientific articles on biological and clinical aspects of ageing are often published in highly ranked scientific journals. That such growing knowledge about ageing has yet to be translated to the care of older patients with complex multimorbidity and frailty is disconcerting, and it therefore might be useful to speculate on why this is the case. For almost a century, most of medical diagnosis, prevention, and treatment have focused on specific diseases. Educational systems, medical departments, and research institutes, as well as the process for approval of new diagnostics and therapeutics, are organised around a disease model. Only relatively recently has the medical community recognised that patients with multiple comorbidities absorb the bulk of resources in the medical system.4Cassell A Edwards D Harshfield A et al.The epidemiology of multimorbidity in primary care: a retrospective cohort study.Br J Gen Pract. 2018; 68: e245-e251Crossref PubMed Scopus (185) Google Scholar In older patients, multimorbidity is not merely the stochastic co-emergence of multiple medical conditions that, at least apparently, have different pathophysiologies. Rather, there is evidence that some individuals have a global susceptibility to multiple diseases. Finally, although the accumulation of pathology occurs progressively over the lifetime, the diagnosis of diseases only becomes possible when the accumulation of pathology is beyond the threshold of compensation and the signs, symptoms, and functional impairments become manifest. Thus, most patients (older and younger) who approach the medical system because of alarm signs or symptoms are likely to be affected by other subclinical pathologies. Because of the mantra one symptom—one disease emphasised in medical education and the increasingly shorter time that physicians can dedicate to patients, hidden comorbidity is often ignored until it is no longer silent, and patients come back to the medical system with complex multimorbidity, or even frailty. Our ability to offer cures and care for such patients is, at best, mediocre.5Walston J Bandeen-Roche K Buta B et al.Moving frailty toward clinical practice: NIA Intramural Frailty Science Symposium summary.J Am Geriatr Soc. 2019; 67: 1559-1564Crossref PubMed Scopus (82) Google Scholar Only over the past 10 years have the guidelines for the diagnosis and treatment of specific diseases developed by medical societies begun to account for co-morbididity, but such guidelines almost never account for multimorbidity. There is evidence that comorbidity, especially in older people who also have physical and cognitive impairments, hides the clinical presentation of emerging pathology, blunts responses to treatment, and results in unexpected adverse outcomes, sometimes even because of iatrogenesis.6Whitty CJM MacEwen C Goddard A et al.Rising to the challenge of multimorbidity.BMJ. 2020; 368: l6964Crossref PubMed Scopus (91) Google Scholar The treatment of older patients with complex multimorbidity and frailty is a challenge for health-care systems around the world. Yet, emerging technology and new research give rise to some hope for the future. The movement of so-called geroscience proposes that multimorbidity and frailty are the cumulative expression of ageing and that understanding the biological mechanisms of ageing will open the door to new therapeutic possibilities.7Sierra F Caspi A Fortinsky RH et al.Moving geroscience from the bench to clinical care and health policy.J Am Geriatr Soc. 2021; 69: 2455-2463Crossref PubMed Scopus (10) Google Scholar Expanding the clinical use of deficit accumulation indexes (DAIs) might be a first step in the right direction.8Rockwood K Mitnitski A Frailty in relation to the accumulation of deficits.J Gerontol A Biol Sci Med Sci. 2007; 62: 722-727Crossref PubMed Scopus (1491) Google Scholar DAIs are agnostic regarding which diseases and health deficiencies are present and provide a global metric of health that can alert clinicians to possible impending health deterioration. At the global level, these indices can help to uncover health disparities in particular groups and inform clinical guidelines and policies. However, there is growing evidence that diseases emerge in clusters, not necessarily due to a common cause (other than ageing per se), and identification of these clusters would be another important tool in the clinical management of older people.9Vetrano DL Roso-Llorach A Fernández S et al.Twelve-year clinical trajectories of multimorbidity in a population of older adults.Nat Commun. 2020; 11: 3223Crossref PubMed Scopus (49) Google Scholar For example, clinical trials that use metformin as a geroprotector,10Wang C-P Lorenzo C Habib SL Jo B Espinoza SE Differential effects of metformin on age related comorbidities in older men with type 2 diabetes.J Diabetes Complications. 2017; 31: 679-686Crossref PubMed Scopus (69) Google Scholar, 11Kulkarni AS Aleksic S Berger DM Sierra F Kuchel GA Barzilai N Geroscience-guided repurposing of FDA-approved drugs to target aging: a proposed process and prioritization.Aging Cell. 2022; 21: e13596Crossref PubMed Scopus (3) Google Scholar such as the TAME trial, consider multimorbidity as one of the primary outcomes. Looking at specific clusters of coexisting diseases identified in large epidemiological studies might be important to better define the outcomes of these trials. Translating measures of the fundamental mechanisms of ageing, identified as the hallmarks or pillars of ageing,12López-Otín C Blasco MA Partridge L Serrano M Kroemer G The hallmarks of aging.Cell. 2013; 153: 1194-1217Summary Full Text Full Text PDF PubMed Scopus (7255) Google Scholar to humans also has great potential. We can now quantify thousands of proteins, metabolites, and other biomarkers in a few drops of blood, and algorithms for the detection of many different chronic diseases, as well as accelerated ageing based on these biomarkers, are being developed and validated in large populations. Specificity and predictive value are being replicated in multiple populations, suggesting that their application to clinical practice is getting closer.13Rutledge J Oh H Wyss-Coray T Measuring biological age using omics data.Nat Rev Genet. 2022; 10 (published online June 17.)https://doi.org/10.1038/s41576-022-00511-7Google Scholar If the technologies for assessing these biomarkers could be scaled up to be relatively inexpensive and high throughput, these biomarkers could be routinely applied to all people who contact a health professional because of an emerging medical problem. The information collected from these biomarkers and other technologies, as well as therapeutic choices and outcomes, could be fed to an artificial intelligence (AI) system that over time sorts what has worked from what has not, even for an individual, to progressively enhance the diagnostic and therapeutic value of longitudinally collected information. In the future, this powerful information system could also provide more information pertaining to the expected outcomes of different therapeutic choices to health-care professionals and patients so they can make more informed decisions. Introducing a time dimension into clinical assessment is possibly the most important reason for having access to electronic medical records. Enhancing health care through personalised medicine, each patient could be viewed as a longitudinal case study, with the expectation that monitoring the change of a clinical value, even within normal values, would reveal and allow for addressing subclinical morbidities. Given the possible feedback loop between morbidity and the rate of ageing, addressing incipient disease in the preclinical period might be a powerful strategy to slow down the rate of ageing and prevent or delay its deleterious consequences. Over time, treatment approaches that result in poor outcomes could be weeded out and new therapeutic approaches that become available can be tested in real-world situations. Those who care for older adults are fully aware that behavioural, social, and environmental factors can strongly affect the outcomes of older patients with complex multimorbidity and disability and this information could be included in the aforementioned surveillance system. The approach to health and health care described here is quite different from what we have used up to this point, but new problems call for new solutions. Early detection of subclinical pathology and the development of biomarkers that capture the rate of ageing are powerful assets that might expand prevention beyond the boundaries of specific diseases and provide people with additional years of healthy life. An approach to health problems that is not based on disease nosology, but rather biomarker algorithms constantly refined by an AI-based surveillance system, might also provide a better approach to the care of older patients with incipient or presenting complex multimorbidity and disability. Thus, the tools to face the challenge posed by complex older patients with multimorbidity and frailty are potentially already available, and what is needed is a strong push for their translation to clinical application and care. A crucial step is to close the gap between the so-called geroscientists and the health professionals who take care of older patients. We have all heard or read that "these new findings have strong translational potential", but in most instances there are no geriatricians or other health professionals among the audience or readership to react to these statements. Finding new and more efficient ways to connect basic research on ageing with the care of older patients is essential to orient research in the right direction and toward topics that hamper the successful care of older patients. Only those who deal daily with the complexity of problems presented by these patients can provide this information. Geriatricians, health-care providers, and patients should be the primary beneficiaries of this science and, therefore, it seems logical that they should be strongly involved as soon as possible. These few considerations represent what we believe is a roadmap to make progress in this field, but we call for visionary researchers to provide new ideas for the development of novel programs that might improve the health and quality of life in this patient population, which will exponentially grow in the future. It is already late, and we should not wait any longer to have this discussion. We declare no competing interests. This work was supported by the Intramural and Extramural Program of the National Institute on Aging. The authors thank Siobhan Addie for assistance with the manuscript and Josephine Egan for providing comments on the final manuscript.